Cerebral accidents (such as stroke), especially ischemic apoplexy, is currently the third biggest cause of death. It is also the major factor that causes long-term loss of living abilities. In developed countries, strokes make up 10% of the death among men and 17% of the death among women. With the aging of population, it is predicted that there will be a rise of 13% in stroke patients during the next 3 years. Three fourths of stroke survivors will be disabled or dysfunctional, which results in highly increased medical cost and other serious social problems.
There are now two kinds of therapeutic medicines for the treatment of ischemic apoplexy:
1. Drugs, which induce the ischemia areas to reperfusion, and open up blocked blood vessels, resulting in recovery of cerebral blood flow, and survival of ischemic brain tissue. These agents are mainly thrombolytics, anticoagulants, vasodilators, radical cleansers, brain function accelerants and thrombolytic compositions of Chinese medicines.
2. Neuroprotective agents, which prevent damage to nerves caused by ischemia during the early stage of acute ischemic apoplexy.
The safety and efficiency of the first category of medicines are controversial, especially because of individual differences of patients. In particular, some of the drugs may cause unwanted bleeding aggravating ischemia and its symptoms and increasing the early stage mortality rate. Therefore, their clinical use has been limited.
The second category of medicines is neuroprotecting agents. Studies show that when the brain is in an ischemic state, Excitatory Amino Acid (EAA), a central neurotransmitter, is released in large amounts, acts on EAA receptors, mostly on the effector-comlex (N-methyl-D-aspartate receptor, NMDA receptor), and then opens the Ca2+ and Na2+ channels, changes the ion permeability, and causes imbalance of the ions inside and outside of the neural cells. This primarily will result in large in-flow the Ca2+ and Na2+, which causes swelling and death of nerve cells. In theory, if the activity of NMDA receptor is inhibited partly, the in-flow of Ca2+ can be reduced greatly, and then the ischemic brain injury induced by NMDA receptor will be effectively prevented.
Recent discoveries of different kinds of EAA receptor antagonists have enabled a new approach to treating ischemic brain injuries. Among them, NMDA receptor antagonists are the main candidates for developing new drugs for preventing and treating ischemic apoplexy. Many NMDA receptor antagonists such as GV-150526A, AR-R15896, ACEA-1021, and ZD-9379 are being tested in clinical phases.
NMDA receptor competitive antagonists have two acid groups and high polarity, and are hard to permeate the blood-brain barrier. Their oral bioavailability is low. The piperazine derivative CPP and its analogues are highly selective, strong receptor antagonists, can permeate the blood-brain barrier and have activity after oral administration (Fritz, K. I., Brain Res. 729(1) 66-74, 1996). Ly-274614 is now one of the most effective NMDA receptor competitive antagonists (Cheung, N. S., Eur. J. Pharmacol., 313(1/2), 159-162, 1996). However, the above-mentioned antagonists have low therapeutic index, with side effects such as damages to motor neuron.
Disjunctive anesthetics acting on cation channel such as PCP and MK-801 are all non-competitive antagonists. These non-competitive antagonists can easily permeate the blood brain barrier; however, they have low selectivity and serious toxicity. Thus they have no or little clinical value.
Since the 1990s, new compounds have been continuously entering clinical trials. It is a long and hard task in this research area to design and synthesize selective and effective NMDA receptor modulators, and the novel antagonists with the lowest psychic and mental toxicities. This task also has great social and economic values.